{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T03:32:00Z","timestamp":1778556720899,"version":"3.51.4"},"reference-count":24,"publisher":"The Endocrine Society","issue":"6","funder":[{"name":"Italian Ministry of Health","award":["Ricerca Corrente 2011 and 2012"],"award-info":[{"award-number":["Ricerca Corrente 2011 and 2012"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["FP6 EUGENE2 Grant LSHM-CT-2004-512013"],"award-info":[{"award-number":["FP6 EUGENE2 Grant LSHM-CT-2004-512013"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Rome \u201cSapienza\u201d"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,1]]},"abstract":"<jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>Reduced insulin signaling in insulin secreting \u03b2-cells causes defective insulin secretion and hyperglycemia in mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design:<\/jats:title>\n                  <jats:p>Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and\/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03\u20131.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R2 = 0.80, P &lt; .001).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces \u03b2-cell function and impairs glucose homeostasis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2012-4282","type":"journal-article","created":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T11:29:44Z","timestamp":1367407784000},"page":"E1143-E1147","source":"Crossref","is-referenced-by-count":14,"title":["Joint Effect of Insulin Signaling Genes on Insulin Secretion and Glucose\n          Homeostasis"],"prefix":"10.1210","volume":"98","author":[{"given":"Sabrina","family":"Prudente","sequence":"first","affiliation":[{"name":"Casa Sollievo della Sofferenza-Mendel Laboratory (S.P., D.B., F.A., V.T.), 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Morini","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (E.M., V.T.), \u201cSapienza\u201d University, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorella","family":"Marselli","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism (L.M., P.M.), University of Pisa, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Baratta","sequence":"additional","affiliation":[{"name":"Departement of Molecular and Clinical Biomedicine (R.B., L.F.), University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimiliano","family":"Copetti","sequence":"additional","affiliation":[{"name":"Unit of Biostatistics (M.C., F.P.), and Research Unit of Diabetes, 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Mendonca","sequence":"additional","affiliation":[{"name":"Research Division (C.M., H.S., A.D.), Joslin Diabetes Center, Boston, Massachusetts 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Andreozzi","sequence":"additional","affiliation":[{"name":"Casa Sollievo della Sofferenza-Mendel Laboratory (S.P., D.B., F.A., V.T.), 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manisha","family":"Chandalia","sequence":"additional","affiliation":[{"name":"Unit of Biostatistics (M.C., F.P.), and Research Unit of Diabetes, 71013 San Giovanni Rotondo, Italy"},{"name":"Department of Medicine (M.C., N.A.), Division of Endocrinology and Metabolism and The Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Unit of Biostatistics (M.C., F.P.), and Research Unit of Diabetes, 71013 San Giovanni Rotondo, Italy"},{"name":"Unit of Biostatistics (F.P.), Consorzio Mario Negri Sud, 66030 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Bailetti","sequence":"additional","affiliation":[{"name":"Casa Sollievo della Sofferenza-Mendel Laboratory (S.P., D.B., F.A., V.T.), 71013 San Giovanni Rotondo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Alberico","sequence":"additional","affiliation":[{"name":"Casa Sollievo della Sofferenza-Mendel Laboratory (S.P., D.B., F.A., V.T.), 71013 San Giovanni Rotondo, Italy"},{"name":"Department of Medical and Surgical Sciences (F.A., G.S.), University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hetal","family":"Shah","sequence":"additional","affiliation":[{"name":"Research Division (C.M., H.S., A.D.), Joslin Diabetes Center, Boston, Massachusetts 02215"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Abate","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.C., N.A.), Division of Endocrinology and Metabolism and The Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Sesti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (F.A., G.S.), University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Frittitta","sequence":"additional","affiliation":[{"name":"Departement of Molecular and Clinical Biomedicine (R.B., L.F.), University of Catania, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piero","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism (L.M., P.M.), University of Pisa, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Doria","sequence":"additional","affiliation":[{"name":"Research Division (C.M., H.S., A.D.), Joslin Diabetes Center, Boston, Massachusetts 02215"},{"name":"Department of Medicine (A.D.), Harvard Medical School, Boston, Massachusetts 02114"},{"name":"Department of Epidemiology (A.D.), Harvard School of Public Health, Boston, Massachusetts 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Trischitta","sequence":"additional","affiliation":[{"name":"Casa Sollievo della Sofferenza-Mendel Laboratory (S.P., D.B., F.A., V.T.), 71013 San Giovanni Rotondo, Italy"},{"name":"Endocrine Diseases (V.T.), Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy"},{"name":"Department of Experimental Medicine (E.M., V.T.), \u201cSapienza\u201d University, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2013,6,1]]},"reference":[{"key":"2019081407145860200_B1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.2337\/diab.43.8.1066","article-title":"Banting Lecture. 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Evidence from transfection studies","volume":"97","author":"Almind","year":"1996","journal-title":"J Clin Invest"},{"key":"2019081407145860200_B11","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nrendo.2009.215","article-title":"Insulin signaling regulating genes: effect on T2DM and cardiovascular\n            risk","volume":"5","author":"Prudente","year":"2009","journal-title":"Nat Rev Endocrinol"},{"key":"2019081407145860200_B12","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1161\/01.CIR.0000109498.77895.6F","article-title":"G972R IRS-1 variant impairs insulin regulation\n            of endothelial nitric oxide synthase in cultured human endothelial\n          cells","volume":"109","author":"Federici","year":"2004","journal-title":"Circulation"},{"key":"2019081407145860200_B13","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.2337\/diabetes.54.9.2807","article-title":"The functional Q84R polymorphism of\n            mammalian Tribbles homolog TRB3 is associated with insulin resistance and related\n            cardiovascular risk in Caucasians from Italy","volume":"54","author":"Prudente","year":"2005","journal-title":"Diabetes"},{"key":"2019081407145860200_B14","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1161\/ATVBAHA.108.162883","article-title":"TRIB3 R84 variant is associated\n            with impaired insulin-mediated nitric oxide production in human endothelial\n            cells","volume":"28","author":"Andreozzi","year":"2008","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2019081407145860200_B15","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1172\/JCI36849","article-title":"The pseudokinase tribbles homolog 3\n            interacts with ATF4 to negatively regulate insulin exocytosis in human and mouse \u03b2\n            cells","volume":"120","author":"Liew","year":"2010","journal-title":"J Clin 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